Anthracyclines with unusually high activity against cells resistant to doxorubicin and its analogs

Abstract

The present disclosure details novel modified anthracyclines, the synthesis thereof, and their use in treating patients with tumors. Preferred aspects of the disclosure involve modified anthracyclines which have an O-substituted aromatic ring on their sugar moiety. Other preferred aspects of the disclosure involve synthesis steps wherein a hydroxyl group on a sugar moiety to be added is blocked with a halo-substituted alkyl group during the process of adding it to an anthracycline ring compound.

What is claimed is: 
     
       1. A compound having a formula: ##STR5## wherein, R 1  is a hydrogen, hydroxyl, acylated hydroxyl, alkyl, arylalkyl or alkyl in ester linkage group; R 2  is CH 2  --AR, where Ar is defined as being an aryl group;   R 3  is a hydrogen or OCH 3  group;   R 4  and R 5  are either hydrogen or hydroxyl groups;   X is an alkyl group; and   the compound demonstrates the ability to kill a doxorubicin-resistant tumor cell.   
     
     
       2. The compound of claim 1, wherein Ar is a phenyl ring. 
     
     
       3. The compound of claim 1, wherein R 1  is a hydroxyl group. 
     
     
       4. The compound of claim 3, wherein the R 1  hydroxyl group is acylated. 
     
     
       5. The compound of claim 4, wherein the acyl group is valerate. 
     
     
       6. The compound of claim 1, wherein X is a methyl group. 
     
     
       7. The compound of claim 1, wherein X is a methyl group and Ar is a phenyl group. 
     
     
       8. The compound of claim 7, wherein R 1  is a hydroxyl group. 
     
     
       9. The compound of claim 8, wherein R 1  is a hydroxyl group that is acylated with an acyl group. 
     
     
       10. The compound of claim 9, wherein the acyl group is valerate. 
     
     
       11. An anthracycline preparable by adding electrophilically, 3-O-benzyl-L-fucal in which a hydroxyl group at C-4 is blocked with a halosubstituted acyl group, to an anthracyclinone. 
     
     
       12. A compound having a formula: ##STR6## wherein R 1  is a hydrogen or hydroxyl group; R 2  is CH 2  --Ar, where Ar is an aryl group;   R 3  is a hydrogen or OCH 3  group;   R 4  is either a hydrogen or hydroxyl group;   R 5  is either a hydrogen or hydroxyl group; and   X is either a methyl group or a fluoro-methyl group.   
     
     
       13. The compound of claim 12, further defined as being 7-O-(3-O-benzyl-2, 6-dideoxy-α-L-lyxo-hexopyranosyl) adriamycinone. 
     
     
       14. The compound of claim 12, further defined as being 7-O-(3-O-benzyl-2,6-dideoxy-α-L-lyxo-hexopyranosyl)-14-O-valeroyl-adriamycinone. 
     
     
       15. The compound of claim 12, wherein R 1  is a hydroxyl group. 
     
     
       16. The compound of claim 15, wherein the R 1  hydroxyl group is an acylated hydroxyl group and the acyl group is valerate. 
     
     
       17. A compound further defined as 7-O-(3-O-benzyl-2, 6-dideoxy-α-L-lyxo-hexopyranosyl) adriamycinone (WP 546) or 7-O-(3-O-benzyl-2,6-dideoxy-α-L-lyxo-hexopyranosyl)-14-O-valeroyl-adriamycinone (WP 549). 
     
     
       18. The compound of claim 17, further defined as 7-O-(3-O-benzyl-2, 6-dideoxy-α-L-lyxo-hexopyranosyl) adriamycinone (WP 546). 
     
     
       19. The compound of claim 17, further defined as 7-O-(3-O-benzyl-2,6-dideoxy-α-L-lyxo-hexopyranosyl)-14-O-valeroyl-adriamycinone (WP 549).